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MCB 137, Homework 2 solution

Problem 1:
(a) Reproduce the model:

Figure : The benzene model. Parent model (left), submodel for the non-fatty tissues (upper middle),
fatty tissues (lower middle), and liver (right).

(b) The benzene concentration in the fatty tissue, Cf, has a much larger scale than the
other concentrations. It is easier to see the dynamic evolution of all concentrations, when
Cf is plotted against the other axis.

Figure : Simulation result of 48 hour exposure of air containing 0.32 mgL-1 of benzene. The yellow
line (non-fatty tissue) is overlapped by the blue line (blood).

(c) Take the half-time as the equilibration time. After zooming in the graph, the
equilibration time can be more accurately measured. Results shown in the table below.
Maximum benzene Equilibration time Equilibration time
conc. (mg/L) (rising phase) (hr) (falling phase) (hr)

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Blood 1.97 0.45 0.33
Non-fatty tissues 1.97 0.52 0.39
Fatty tissues 55.27 2.27 1.8
Liver 2.27 1.45 0.18

The maximum benzene concentration is determined by the benzene solubility of the


tissues. The fatty tissues have much higher benzene solubility than the other tissues, so
the maximum benzene concentration is an order of magnitude larger.

Figure : Zoom-in view of the rising phase.

In the rising phase, the blood equilibrates fastest, followed by the non-fatty tissues, liver
and fatty tissues. The blood benzene concentration rises first because this is the only
compartment connected to the input end. The increase of the blood benzene concentration
leads the benzene increases in the other compartments. The flow rates to the non-fatty
tissues, liver and fatty tissues descend in order, so do their equilibration times.

Figure : Zoom-in view of the falling phase.

In the falling phase, all the other observations are the same, except that liver now
equilibrates fastest. This is because liver is the only exit of benzene. The decreases of
benzene concentration in the other compartments are led by the liver. The role that liver
plays in this phase is similar to the role that blood plays in the rising phase.

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Bonus question:

From the model, we can learn that the fatty tissues, due to the high benzene solubility, are
the tissues that accumulate the most toxicant. If we assume the harm of benzene to a
tissue is proportional to its concentration, then benzene probably does much more harm
to the fatty tissues.

Problem 2:
(a) Reproduce the model

Figure : The model for steroid regulation of histamine. Flowchart (left) and result of simulation with
Dose = 4*104 µg (right). The plot shows Ch, the histamine concentration, and p, the inhibited
percentage of the rate that white blood cells enter the blood. The histamine level starts recovering
when the inhibited percentage drops back to about 2/3 of its maximum level.

(b) Consider the system before the drug is administered. It should rest in a steady state
determined by the equations, where Dose is set to 0. Under this circumstance, the steroid
amount is 0 and the histamine level is determined by the equilibrium of the inflow and
outflow at base rates. Such steady state should serve as the initial values for the system
after the drug is applied, i.e. Init H = 90 µg = Hss.

Note that before drug is applied p = 0.

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(c) Overlay plot of different doses

Figure : Overlaid plots of dosage 4, 10, 20, 40, 80 * 104 µg.

(d) Comparison between steroid percentage and inhibition effect

Figure : The plot of steroid percentage and inhibition effect vs time. The inhibition effect continues
rising until the steroid has been metabolized by ~99%.
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Bonus:

The discrepancy between the time evolution of the inhibition effect and the drug
concentration is due to two reasons.
1. The drug inhibits the trafficking-regulatory enzyme with saturation. The dosage is
itself more than 100 folds larger than the half-saturating concentration (Dose/Vd
= 40000/90 > K50*100). Thus before the drug is metabolized by ~99%, the
inhibition takes effect at almost the maximum level. Only after that does the
inhibition starts to wane.
2. The inhibition is acted on the flow entering H, so it takes time for H to recover
even if the inhibition is lifted right away. This time is characterized by the time
constant of the equation that governs H, Vd/kh = 14.7 hr. However, after reaching
maximum, H decreases slower than this characteristic time (half time ~ 15hr >
14.7*0.67 hr). This is because the inhibition still acts on the inflow of H, though
with diminished effect. The relaxation is thus delayed.

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